Scaffold Hopping Toward Agomelatine: Novel 3, 4-Dihydroisoquinoline Compounds as Potential Antidepressant Agents

Abstract

A scaffold-hopping strategy toward Agomelatine based on in silico screening and knowledge analysis was employed to design novel antidepressant agents. A series of 3, 4-dihydroisoquinoline compounds were selected for chemical synthesis and biological assessment. Three compounds (6a-1, 6a-2, 6a-9) demonstrated protective effects on corticosterone-induced lesion of PC12 cells. Compound 6a-1 also displayed low inhibitory effects on the growth of HEK293 and L02 normal cells and it was further evaluated for its potential antidepressant effects in vivo. The forced swim test (FST) results revealed that compound 6a-1 remarkably reduced the immobility time of rats and the open field test (OFT) results indicated a better general locomotor activity of the rats treated with compound 6a-1 than those with Agomelatine or Fluoxetine. Mechanism studies implied that compound 6a-1 can significantly reduce PC12 cell apoptosis by up-regulation of GSH and down-regulation of ROS in corticosterone-induced lesion of PC12 cells. Meanwhile, the down-regulation of calcium ion concentration and up-regulation of BDNF level in PC12 cells may account for the neuroprotective effects. Furthermore, compound 6a-1 can increase cell survival and cell proliferation, promote cell maturation in the rat hippocampus after chronic treatment. The acute toxicity data in vivo indicated compound 6a-1 exhibited less hepatotoxicity than Agomelatine.

5-HTT independent effects of fluoxetine on neuroplasticity

“…Although widely investigated in in vivo conditions 31–33 , the in vitro effects of fluoxetine on Bdnf mRNA expression have been reported in only a few studies. All showed that fluoxetine can activate Bdnf expression, in control conditions, as well as in stressful environments, such as under toxic conditions induced by B27 deprivation in primary rat hippocampal cultures 34 or in corticosterone-exposed PC12 cells 35 . We further confirmed and complemented those data showing that fluoxetine induces Bdnf mRNA expression and also activates immediate early gene expression, such as Egr1 and Cfos , and stimulates TrkB phosphorylation in C57Bl/6J primary cortical cell cultures.…”

Fluoxetine treatment for more than 2 days decreases the cellular neuroplasticity and microtubule plasticity in differentiated PC12 cells

“…The previous studies [3,[24][25][26] treated with FLU for time periods ranging from 1 day to 2 days, while we medicated with FLU for longer periods up to 3 days. This prolonged period found treatment with FLU has an opposite effects on the regulation of cellular neuroplasticity and microtubule plasticity at 1 day than at 3 days.…”

“…The growth state of cells or cell viability played an important role in this phenomenon. Almost all of previous studies [3,[24][25][26] regard treated with drugs from 1 day to 2 days as treatment models of antidepressants, during which the cells are in the growth phase or stable phase. The cells maintain high cell viability, which is consistent with the results of this study.…”

“…Upon the nerve growth factor stimulation, PC12 cells are differentiated and display neurite growth [18,21,22], which [23] is advantageous for the study of neuronal plasticity and express tubulin. Since almost all of those studies [3,[24][25][26] treated with drugs for 1 to 2 days as treatment models of antidepressants, we hypothesized that antidepressant treatment for longer periods would have opposite effects on neuroplasticity and microtubule plasticity. To test this hypothesis, we administered FLU from 1 day to 3 days to study the effects on the cellular neuroplasticity and microtubule plasticity in PC12 cells.…”

Facile Route to the Synthesis of 1,3-Diazahetero-Cycle-Fused [1,2-a]Quinoline Derivatives via Cascade Reactions

“…Quinolines is an important class of well-known heterocyclic scaffolds; they are embedded in many biological systems and have interesting applications in agriculture, materials, chemical industry, and medicine, for instance, as antimalarial (Figure , quinine), , anticancer (Figure , camptothecin), antibacterial, , insecticide (Figure , quinclorac), and so forth. − Consequently, various methods of synthesis of quinolines have been reported. − Among them, the transition-metal-catalyzed C–H bond or N–H bond activation approaches have provided numerous strategies for the synthesis of quinoline. − …”